Biomedicines

14 pages, 418 KB

Open AccessArticle

The Impact of the COVID-19 Pandemic on Coronary Artery Bypass Grafting Surgery: A Single-Centre Retrospective Cohort Study

by Paweł Nadziakiewicz and Marta Wajda-Pokrontka

Biomedicines 2025, 13(9), 2264; https://doi.org/10.3390/biomedicines13092264 (registering DOI) - 14 Sep 2025

Abstract

Background/Objectives: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cardiac surgery, limiting patient access and altering care quality. This study evaluates changes in cardiovascular disease severity, types, and postoperative complications in patients qualifying for coronary artery bypass grafting (CABG) during the pandemic. Methods: [...] Read more.

Background/Objectives: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cardiac surgery, limiting patient access and altering care quality. This study evaluates changes in cardiovascular disease severity, types, and postoperative complications in patients qualifying for coronary artery bypass grafting (CABG) during the pandemic. Methods: We performed a retrospective analysis of 1499 CABG patients at our institution between March 2018 and February 2022. Patients were categorised into two groups: pre-pandemic (March 2018 to February 2020, N = 853) and pandemic (March 2020 to February 2022, N = 646). We analysed and detailed data across three major COVID-19 waves in Poland. Results: During the COVID-19 pandemic, 646 patients underwent CABG, a 24.3% decline from 853 pre-pandemic procedures. Urgent procedures increased from 37.6% to 44%, and life-saving procedures rose from 2.9% to 5.2% (p < 0.05). The use of cardiopulmonary bypass increased, along with longer procedure times (median of 279.7 min vs. 315 min; p < 0.001). The duration of mechanical ventilation increased during the pandemic period (median 12 h vs. 11 h; p < 0.05). No significant differences in postoperative complications were noted. Analysis during the three COVID-19 waves showed consistent baseline characteristics. In the second wave, life-saving CABG procedures reached 11.4%, with 17.5% of patients presenting acute coronary symptoms. Conclusions: The COVID-19 pandemic reduced CABG procedures, prioritising urgent cases. Short-term mortality odds rose, despite unchanged patient risk profiles. More multicentre research is needed to understand resource constraints on cardiac surgical outcomes and to establish guidelines for patient prioritisation in future pandemics. Full article

(This article belongs to the Special Issue Coronary Artery Disease: From Pathophysiology to Therapeutic Strategies)

19 pages, 1788 KB

Open AccessArticle

Transcriptomic Profile of Isocitrate Dehydrogenase Mutant Type of Lower-Grade Glioma Reveals Molecular Changes for Prognosis

by Seong Beom Cho

Biomedicines 2025, 13(9), 2263; https://doi.org/10.3390/biomedicines13092263 (registering DOI) - 14 Sep 2025

Abstract

Background/Objectives: Lower-grade glioma (LGG) is a type of brain tumor with a relatively better prognosis than glioblastoma. However, identifying therapeutic targets for LGGs remains elusive. To uncover the molecular features of LGGs, functional genomics data have been investigated. Methods: Using public transcriptomics [...] Read more.

Background/Objectives: Lower-grade glioma (LGG) is a type of brain tumor with a relatively better prognosis than glioblastoma. However, identifying therapeutic targets for LGGs remains elusive. To uncover the molecular features of LGGs, functional genomics data have been investigated. Methods: Using public transcriptomics data of LGGs (The Cancer Genome Atlas and GSE107850), differentially expressed genes (DEGs) and differentially co-expressed (DCE) gene pairs between IDH mutation statuses were determined. Gene set enrichment analysis identified the molecular mechanisms of isocitrate dehydrogenase (IDH) mutation in LGGs. Furthermore, the identified DEGs and DCE gene pairs were used for drug repurposing analysis. Results: Two public datasets revealed an overlap of 1527 DEGs. Whereas only seven gene pairs showed significant differential co-expression in both datasets, 1016 genes were simultaneously involved in differential co-expression. Gene set enrichment revealed that biological processes related to neuronal tissue formation were significantly associated with the DEGs. Using drug repurposing analysis, it was found that NVP-TAE684 and bisindolylmaleimide were possible chemical compounds for the LGG treatment. Conclusions: Using transcriptomics data, molecular mechanisms associated with LGG prognosis were identified. This work provides clues for future research on LGG treatment. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

14 pages, 771 KB

Open AccessReview

Gut Microbiome-Mediated Genetic and Epigenetic Alterations in Colorectal Cancer: Population-Specific Insights

by Simona Turcu, Florin Grama and Maria Gazouli

Biomedicines 2025, 13(9), 2262; https://doi.org/10.3390/biomedicines13092262 (registering DOI) - 14 Sep 2025

Abstract

Colorectal cancer (CRC) remains a major global challenge, with growing attention to its pathogenesis as mediated by the gut microbiome and epigenetic regulation. Despite therapeutic progress, clinical management remains difficult. CRC accounts for ~10% of cancers and is the second leading cause of [...] Read more.

Colorectal cancer (CRC) remains a major global challenge, with growing attention to its pathogenesis as mediated by the gut microbiome and epigenetic regulation. Despite therapeutic progress, clinical management remains difficult. CRC accounts for ~10% of cancers and is the second leading cause of cancer death worldwide. Romania bears a substantial burden, with many diagnoses at advanced stages. Etiology—Integrated Genetic, Environmental, and Microbial Determinants. Hereditary syndromes explain 10–15% of cases; most are sporadic, with hypermutated MSI/POLE (~15%), non-hypermutated chromosomal instability (~85%), and a CpG island methylator phenotype (~20%). GWAS implicate loci near SMAD7, TCF7L2, and CDH1; in Romania, SMAD7 rs4939827 associates with risk. Lifestyle exposures—high red/processed meat, low fiber, adiposity, alcohol, and smoking—shape susceptibility. Microbiome–Epigenome Interactions. Dysbiosis promotes carcinogenesis via genotoxins (e.g., colibactin), hydrogen sulfide, activation of NF-κB/STAT3, barrier disruption, and epigenetic remodeling of DNA methylation and microRNAs. Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks⁺ Escherichia coli exemplifies these links. Population-Specific Risk—Romania within Lifestyle–Microbiome Evidence. Incidence is rising, including early-onset disease. Romania lacks CRC-specific microbiome datasets. However, metabolic cohorts show loss of butyrate producers, enrichment of pathobionts, and SCFA imbalance—patterns that mirror European CRC cohorts—and exhibit regional heterogeneity. Beyond Fusobacterium nucleatum. Additional oncobacteria shape tumor biology. Peptostreptococcus stomatis activates integrin α6/β4→ERBB2–MAPK and can bypass targeted inhibitors, while Parvimonas micra enhances WNT/β-catenin programs and Th17-skewed immunity. Together, these data support a systems view in which microbial cues and host epigenetic control jointly drive CRC initiation, progression, metastasis, and treatment response. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)

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14 pages, 263 KB

Open AccessArticle

Exploring the Link Between Obstructive Sleep Apnea and Diabetes Mellitus: A Retrospective Single-Center Analysis

by Mara Andreea Vultur, Dragoș Huțanu, Edith Simona Ianoși, Hédi-Katalin Sárközi, Corina Eugenia Budin, Maria Beatrice Ianoși, Mioara Szathmáry and Gabriela Jimborean

Biomedicines 2025, 13(9), 2261; https://doi.org/10.3390/biomedicines13092261 (registering DOI) - 14 Sep 2025

Abstract

Background: Obstructive sleep apnea (OSA) is prevalent and often underdiagnosed, linking to cardiovascular disease, type 2 diabetes mellitus (T2DM), dyslipidemia, and cognitive decline. Coexistence with T2DM worsens patient outcomes. Positive airway pressure (PAP) therapy has demonstrated benefits in improving metabolic parameters and [...] Read more.

Background: Obstructive sleep apnea (OSA) is prevalent and often underdiagnosed, linking to cardiovascular disease, type 2 diabetes mellitus (T2DM), dyslipidemia, and cognitive decline. Coexistence with T2DM worsens patient outcomes. Positive airway pressure (PAP) therapy has demonstrated benefits in improving metabolic parameters and reducing comorbidities. Methods: This study examined the association between OSA and T2DM, focusing on therapy adherence. Overall, 73 patients from the pulmonology department, with diagnosed OSA and T2DM or prediabetes (PD) were compared to 72 OSA patients without diabetes. All underwent cardio-respiratory polygraphy. Data on demographics, comorbidities, and adherence were collected to evaluate disease severity and compliance. Results: Only 24% of patients were referred from cardiology or internal medicine. The STOP-BANG questionnaire accurately identified 83.4% of cases. Of the study group, 65.75% had T2DM, 34.2% had PD, and 16.5% received new diagnoses. T2DM patients had the highest BMI (40.19 kg/m²). Smoking prevalence exceeded European averages. These patients experienced more severe OSA and multiple comorbidities. PAP adherence increased from 73% to 86% after full financial coverage. Conclusions: Polygraphy remains an effective diagnostic tool. Patients with T2DM tend to have more severe OSA and comorbidities, underscoring the importance of early screening and increased awareness to improve management and outcomes. Full article

(This article belongs to the Special Issue Emerging Insights in Thoracic Diseases: From Diagnostics to Biomarkers and Therapeutic Implications Through Interdisciplinarity)

11 pages, 337 KB

Open AccessArticle

Exploring the Associations Between CHRNA5 and IREB2 Gene Polymorphisms and COPD in the Kazakhstan Population

by Almira Akparova, Gaukhar Kurmanova, Gulzhan Trimova, Yeldar Ashirbekov, Diana Nigmatova, Balkiya Abdrakhmanova, Zhanar Mussagulova, Gulzhana Idrisova, Anarkul Kulembayeva and Almagul Kurmanova

Biomedicines 2025, 13(9), 2260; https://doi.org/10.3390/biomedicines13092260 (registering DOI) - 13 Sep 2025

Abstract

Background/Objectives: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterized by irreversible airway obstruction. This study aims to investigate the associations between COPD and its phenotypes with polymorphic variants of the IREB2 and CHRNA5 genes in the Kazakhstan population. [...] Read more.

Background/Objectives: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterized by irreversible airway obstruction. This study aims to investigate the associations between COPD and its phenotypes with polymorphic variants of the IREB2 and CHRNA5 genes in the Kazakhstan population. Methods: A case–control study was conducted involving 265 COPD patients and 267 controls. Genotyping of the IREB2 polymorphisms rs13180 and rs2568494, as well as CHRNA5 rs16969968 polymorphism, was performed using real-time polymerase chain reactions (Real-Time PCRs). Results: A higher frequency of the AA genotype of the IREB2 rs2568494 polymorphism was identified in COPD patients with moderate to very severe airflow obstruction (Chronic Obstructive Lung Disease (GOLD) stages II, III, and IV), with an odds ratio of 0.69 (95% CI = 0.23–2.10; Padj = 0.03). The IREB2 rs13180 polymorphism was significantly more frequent or prevalent in smokers and showed a correlation with FEV₁ (forced expiratory volume in one second) (β = 7.79, SE = 2.98, p = 0.01) and FEV₁/ FVC (forced vital capacity) (β = 9.51, SE = 2.95, p = 0.002). Additionally, the CC genotype of this polymorphism was associated with clinical manifestations of COVID-19 in COPD patients (χ²= 3,95, df = 2, p = 0.05). Conclusions: Our study identified a significant association between the IREB2 rs2568494 polymorphism and an increased risk of severe COPD. The IREB2 rs13180 polymorphism was linked to smoking behavior, as well as key lung function indicators, suggesting its potential role in disease progression and lung damage. Furthermore, the CC genotype of the IREB2 rs13180 polymorphism was associated with clinical manifestations of COVID-19 in COPD patients, indicating a potential impact of this genetic variant on susceptibility to viral infections in this population. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Respiratory Diseases)

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14 pages, 275 KB

Open AccessArticle

Comorbidity Profile of Chronic Mast Cell–Mediated Angioedema Versus Chronic Spontaneous Urticaria

by Eli Magen, Iris Leibovich, Israel Magen, Eugene Merzon, Ilan Green, Avivit Golan-Cohen, Shlomo Vinker and Ariel Israel

Biomedicines 2025, 13(9), 2259; https://doi.org/10.3390/biomedicines13092259 (registering DOI) - 13 Sep 2025

Abstract

Background: Chronic mast cell–mediated angioedema (MC-AE) and chronic spontaneous urticaria (CSU) both involve mast cell activation but may differ in long-term systemic outcomes. Limited data exist comparing their comorbidity profiles over extended follow-up. Objective: To compare systemic comorbidities in patients with chronic MC-AE [...] Read more.

Background: Chronic mast cell–mediated angioedema (MC-AE) and chronic spontaneous urticaria (CSU) both involve mast cell activation but may differ in long-term systemic outcomes. Limited data exist comparing their comorbidity profiles over extended follow-up. Objective: To compare systemic comorbidities in patients with chronic MC-AE versus CSU using a large, population-based dataset. Methods: We conducted a retrospective matched case–control study using electronic health records from Leumit Health Services, a nationwide Israeli health maintenance organization. Patients diagnosed with chronic MC-AE between 2005 and 2023 (n = 2133) were matched 1:1 by age, sex, and year of diagnosis to patients with CSU (n = 2133). Comorbidities were assessed at diagnosis and after a mean follow-up of 10.2 ± 2.9 years. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression was used to assess the association between medications and MC-AE diagnosis. Results: MC-AE patients exhibited significantly higher baseline rates of hypertension (23.8% vs. 18.5%), ischemic heart disease (5.67% vs. 3.84%), and type 2 diabetes (10.45% vs. 6.42%) compared to CSU. These differences persisted or increased at follow-up, including myocardial infarction (4.13% vs. 2.25%) and chronic kidney disease (4.13% vs. 2.91%). CSU patients had consistently higher rates of atopic dermatitis, viral infections, and herpes zoster. Statin use was inversely associated with MC-AE (adjusted OR = 0.63; 95% CI: 0.44–0.90). Conclusions: Chronic MC-AE is associated with a distinct and sustained cardiometabolic and renal comorbidity burden compared to CSU, supporting its classification as a systemic disease phenotype requiring differentiated long-term care. Full article

(This article belongs to the Special Issue Urticaria: New Insights into Pathogenesis, Diagnosis and Therapy)

28 pages, 1417 KB

Open AccessReview

Potential for Therapeutic Alteration of the Underlying Biology of Epilepsy

by Michael R. Sperling, Jurriaan M. Peters, Qian Wu, Michelle Guignet, H. Steve White, Evelyn K. Shih, Leock Y. Ngo, Enrique Carrazana and Adrian L. Rabinowicz

Biomedicines 2025, 13(9), 2258; https://doi.org/10.3390/biomedicines13092258 (registering DOI) - 13 Sep 2025

Abstract

Approximately 30–35% of people with epilepsy experience seizures despite taking antiseizure medications. Recurrent seizures that are independent of status epilepticus can be associated with neuronal injury and structural changes to the brain, as well as diminished cognitive function, mood, and quality of life. [...] Read more.

Approximately 30–35% of people with epilepsy experience seizures despite taking antiseizure medications. Recurrent seizures that are independent of status epilepticus can be associated with neuronal injury and structural changes to the brain, as well as diminished cognitive function, mood, and quality of life. A treatment that alters the underlying biology of epilepsy, thereby reducing the seizure burden and its attendant consequences, would be of great value in preventing these detrimental effects. In this review, we summarize preclinical and clinical research on pharmacological treatments that may favorably alter the underlying biology of epilepsy (i.e., disease modification or antiepileptogenesis). A reduction in seizures over time (e.g., increase in responder rates) or prevention of epilepsy in susceptible individuals has been observed with therapies that target neurotransmission (cenobamate, cannabidiol, vigabatrin, and diazepam nasal spray) and inflammation (everolimus), though evidence is limited and in preliminary stages. Pharmacological treatments that target neuroinflammation and oxidative stress have the potential to modify seizure phenotype and 1 or more comorbidities in preclinical studies (e.g., stress/anxiety and depression). Gene therapies and stem-cell-derived treatments also hold promise in reducing seizure burden in preclinical models, with several therapeutic candidates having advanced to phase 1/2 and 3 clinical trials. Effective disease-modifying strategies in epilepsy might include seizure control with novel antiseizure medications in combination with therapeutic targeting of key pathophysiological mechanisms. Standard criteria and a definition of disease modification should be established. Importantly, given the heterogeneity of the epilepsies, syndrome- or seizure-specific methods and trial design would likely be required. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

28 pages, 8444 KB

Open AccessArticle

The Prognostic Role of IL-6 and RBP4 in Colorectal Cancer

by Małgorzata Żulicka, Daria Piątkowska, Dariusz Grzanka, Klaudia Bonowicz, Dominika Jerka, Maciej Gagat and Paulina Antosik

Biomedicines 2025, 13(9), 2257; https://doi.org/10.3390/biomedicines13092257 (registering DOI) - 13 Sep 2025

Abstract

Background/Objectives: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Inflammation and metabolic dysregulation, particularly those related to obesity, have emerged as critical contributors to CRC progression. Interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4), an adipokine involved in metabolic [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Inflammation and metabolic dysregulation, particularly those related to obesity, have emerged as critical contributors to CRC progression. Interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4), an adipokine involved in metabolic regulation, may be key mediators of these processes. This study aimed to evaluate the expression levels of IL-6 and RBP4 in CRC tissues and their associations with clinicopathological features and overall survival. Furthermore, in silico analyses were performed to explore the molecular networks and signaling pathways related to both biomarkers. Methods: Immunohistochemical staining of IL-6 and RBP4 was conducted in 118 CRC and matched adjacent normal tissues. Expression levels were assessed using the H-score system and correlated with clinical parameters. Survival analysis was performed using Kaplan–Meier curves. In silico analyses were based on RNA-seq data from TCGA and included pathway enrichment, gene co-expression, and protein–protein interaction networks. Results: IL-6 and RBP4 expression were significantly elevated in tumor tissue compared to adjacent normal mucosa. High IL-6 expression correlated with age and obesity measures, while RBP4 expression showed significant associations with pT stage, lymph node involvement, TNM stage, and obesity-related parameters. Kaplan–Meier analyses indicated shorter overall survival in patients with high IL-6 or RBP4 expression. In silico analysis confirmed upregulation of IL6 and RBP4 in CRC and highlighted immune-related pathways for IL-6 and developmental signaling for RBP4. Conclusions: Elevated expression of IL-6 and RBP4 in CRC tissue is associated with adverse clinical features and reduced survival, underscoring their potential role as prognostic biomarkers. These findings support the involvement of inflammation and metabolic dysfunction in CRC progression and suggest IL-6 and RBP4 as candidates for future targeted therapeutic approaches. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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16 pages, 1190 KB

Open AccessArticle

Neuropsychomotor Development of Children Exposed to SARS-CoV-2 in Utero During COVID-19 Pandemic

by Felipe Motta, Maria Eduarda Canellas-de-Castro, Geraldo Magela Fernandes, Lizandra Moura Paravidine Sasaki, David Alves de Araújo Júnior, Alberto Moreno Zaconeta, Ângelo Pereira da Silva, Ciro Martins Gomes, Cleandro Pires Albuquerque, Ismael Artur Costa-Rocha, Janaina Araújo Teixeira Santos, José Alfredo Lacerda De Jesus, Karina Nascimento Costa, Laila Salmen Espindola, Licia Maria Henrique da Mota, Lucas Lauand, Luiz Cláudio Gonçalves de Castro, Marcelo Antônio Pascoal Xavier, Jordana Grazziela Alves Coelho-dos-Reis, Otávio Toledo Nóbrega, Pabline Cavalcante da Silva, Rodrigo de Resende Nery, Wanessa Tavares Santos, Rosana Maria Tristão, Caroline Oliveira Alves, Olindo Assis Martins-Filho and Alexandre Anderson de Sousa Munhoz Soares Show full author list Hide full author list

Biomedicines 2025, 13(9), 2256; https://doi.org/10.3390/biomedicines13092256 (registering DOI) - 12 Sep 2025

Abstract

Introduction: Little is known about the effects of intrauterine exposure to SARS-CoV-2, especially on growth and neurodevelopment in children. Objective: We wished to verify the effect of intrauterine exposure to SARS-CoV-2 on neurological development in children. Methods: Infants born to [...] Read more.

Introduction: Little is known about the effects of intrauterine exposure to SARS-CoV-2, especially on growth and neurodevelopment in children. Objective: We wished to verify the effect of intrauterine exposure to SARS-CoV-2 on neurological development in children. Methods: Infants born to mothers presenting with SARS-CoV-2 infection during pregnancy were enrolled in a prospective descriptive–analytical study involving outpatient appointments performed 6 and 12 months after birth. Their neurological development was assessed using the Bayley-III Scale, using a score of >85 as the cutoff threshold for identifying developmental delay. Differences between groups were assessed through an ANOVA, using Bonferroni correction for multiple comparisons. Regression models were employed to examine the associations between the Bayley-III scores and maternal features. Results: Two hundred and sixty-nine infants were evaluated, most of whom were born full-term and with birth weights appropriate for gestational age at delivery. Developmental delays were observed in 26% of the infants in at least one of the Bayley-III domains. The language domain was particularly affected, with impairments observed in children exposed to SARS-CoV-2 closer to the time of delivery. These findings were statistically significant (p < 0.05). Conclusions: Infants born to mothers presenting with SARS-CoV-2 infection during pregnancy presented developmental delays at 6 and 12 months, particularly in the language domain. These findings reinforce the relevance of long-term clinical follow-ups of newborns exposed to SARS-CoV-2 infection during pregnancy. Full article

(This article belongs to the Special Issue Neonatal Disease: From Pathophysiology to Current and Emerging Therapeutic Approaches (2nd Edition))

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30 pages, 4182 KB

Open AccessArticle

Antimicrobial Resistance of Non-Fermenting Gram-Negative Bacilli in a Multidisciplinary Hospital in Romania

by Miruna-Maria Apetroaei, Mihaela Cristina Negulescu, Sorina Hîncu, Adriana Tăerel, Manuela Ghica, Andreea Letiția Arsene and Denisa Ioana Udeanu

Biomedicines 2025, 13(9), 2255; https://doi.org/10.3390/biomedicines13092255 (registering DOI) - 12 Sep 2025

Abstract

Background: Antimicrobial resistance (AMR) in Acinetobacter spp., Pseudomonas spp., and Stenotrophomonas maltophilia poses a significant risk in healthcare-associated infections. Constant monitoring using quantitative metrics is necessary to direct empirical treatment. Methods: We conducted a retrospective observational study at the Fundeni Clinical Institute, Bucharest, [...] Read more.

Background: Antimicrobial resistance (AMR) in Acinetobacter spp., Pseudomonas spp., and Stenotrophomonas maltophilia poses a significant risk in healthcare-associated infections. Constant monitoring using quantitative metrics is necessary to direct empirical treatment. Methods: We conducted a retrospective observational study at the Fundeni Clinical Institute, Bucharest, Romania, analysing antibiogram data from January 2021 to December 2024. Over 200,000 microbiological records were screened, and 1189 isolates of the three targeted pathogens were included. The Multiple Antibiotic Resistance Index (MARI) was applied to evaluate selective pressure across years, hospital departments, sample types, and hospitalisation categories. Results: Acinetobacter baumannii and Pseudomonas aeruginosa exhibited the highest resistance levels, with median MARI values exceeding 0.25 in 2024, particularly in Intensive Care and Transplant units. In contrast, S. maltophilia showed lower overall MARI values, though resistance variability increased in 2024 (extremes up to 0.30). Notably, resistance to carbapenems in Acinetobacter spp. rebounded in 2024, while Pseudomonas spp. demonstrated a favourable trend of decreasing resistance to several β-lactams. Conclusion: Our findings underscore significant interspecies differences in AMR dynamics and highlight the utility of MARI as a valuable operational indicator. Ongoing local surveillance is needed for refining empirical treatment protocols and informing antimicrobial stewardship in Romanian hospitals. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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10 pages, 627 KB

Open AccessArticle

Evaluation of Cytokine Levels in Cardiac Transthyretin and Immunoglobulin Light Chain Amyloidosis and Their Correlation with Myocardial Inflammatory Cells and MACE

by Nicolas Musigk, Phillip Suwalski, Maximilian Müller, Michele Violano, Karin Klingel, January Weiner 3rd, Dieter Beule, Ulf Landmesser and Bettina Heidecker

Biomedicines 2025, 13(9), 2254; https://doi.org/10.3390/biomedicines13092254 (registering DOI) - 12 Sep 2025

Abstract

Aims: Myocardial inflammation in cardiac amyloidosis is associated with poor clinical outcomes. This study aimed to (a) investigate the relationship between peripheral blood cytokine levels and the presence of inflammatory cells within the myocardium, and to (b) evaluate the potential of cytokines as [...] Read more.

Aims: Myocardial inflammation in cardiac amyloidosis is associated with poor clinical outcomes. This study aimed to (a) investigate the relationship between peripheral blood cytokine levels and the presence of inflammatory cells within the myocardium, and to (b) evaluate the potential of cytokines as predictors of major adverse cardiovascular events (MACE) in transthyretin (ATTR) and immunoglobulin light chain (AL) cardiac amyloidosis. Methods: Peripheral blood samples were collected from 50 patients with cardiac ATTR or AL amyloidosis between 2018 and 2023 at baseline and every three months during follow-up visits. Cytokine analysis was performed using Olink’s Proximity Extension Assay. For MACE prediction analysis, only patients with MACE occurring within ±14 days of a study visit were included (n = 16). Associations were evaluated using linear models. Results: No significant associations were identified between the EMB-confirmed myocardial presence of inflammatory cells and cytokine levels. There was a trend of weak-to-moderate associations between serial blood cytokine levels and MACE, albeit this was non-significant after adjustment for multiple testing (FDR): r² = 0.28 for PON3 (p = 0.00075, FDR = 0.28), SIGLEC1 (p = 0.00077, FDR = 0.28), and IL-6 (p = 0.00086, FDR = 0.31). Conclusions: Peripheral blood cytokine levels were not reliable biomarkers for the myocardial presence of inflammatory cells. PON3, SIGLEC1, and IL-6 demonstrated a statistically non-significant trend of a weak-to-moderate association with MACE in cardiac amyloidosis. Since we recently demonstrated that amyloidosis with an inflammatory component is associated with poor outcomes, these additional findings underscore the need for alternative approaches to identify and manage inflammation in this patient population. Full article

(This article belongs to the Section Cell Biology and Pathology)

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23 pages, 1135 KB

Open AccessReview

Current Concepts in Pathogenesis and Conservative Management of Supraspinous Tendinopathies Using Shockwave Therapy—A Narrative Review of the Literature

by Roxana Nartea, Ioana Ghiorghiu, Maria-Delia Alexe, Gavril Lucian Gheorghievici and Brindusa Ilinca Mitoiu

Biomedicines 2025, 13(9), 2253; https://doi.org/10.3390/biomedicines13092253 (registering DOI) - 12 Sep 2025

Abstract

The supraspinatus has been well studied in recent years, since the rotator cuff muscle is most commonly damaged, affecting the quality of life for patients with tendinopathy. Despite this tiny but crucial muscle being well-described, there is still much left to learn and [...] Read more.

The supraspinatus has been well studied in recent years, since the rotator cuff muscle is most commonly damaged, affecting the quality of life for patients with tendinopathy. Despite this tiny but crucial muscle being well-described, there is still much left to learn and discover, especially because chronic supraspinatus tendinopathy is a common pain syndrome that causes functional and labor disabilities in the population. The present narrative review, including systematic elements from biomechanical and clinical studies, highlights the role of conservative treatment using shockwave therapy. Objectives: We set out to perform a complex analysis of the literature on this topic to identify possible pathophysiological mechanisms that can be used to establish proper therapeutic management, focused specifically on conservative treatment using shockwave therapy. Methods: We researched the medical literature, including clinical studies that met the criteria of being published after 2014. In this review, we described the mechanisms and histological changes in tendinopathy to illustrate the biological effects of shockwave therapy and performed a literature review on its therapeutic effects. Conclusions: The multifaced pathophysiology of supraspinous tendinopathies compromised the healing responses. Recent findings highlight the value of a thorough diagnostic and treatment strategy, with shockwave therapy (ESWT) as a conservative treatment option. According to available data, shockwave therapy has demonstrated significant improvement in function, improving participants’ discomfort, quality of life, and pain relief. It can also be combined with isometric exercise. Given the substantial risk of bias and heterogeneity, our findings should be interpreted cautiously. The need for more research to optimize parameters and provide standardized clinical guidelines is highlighted by the variety of treatment procedures. Improving outcomes in patients with supraspinous tendinopathies will require a better comprehension of the pathology, and individualized treatment needs to be further investigated. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Musculoskeletal Conditions, 3rd Edition)

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17 pages, 2005 KB

Open AccessReview

Exploring Genital Lichen Sclerosus: Navigating from Pathophysiology to Precise Diagnostic Approaches

by Maja Sever, Katarina Trčko, Tanja Zidarič and Tina Maver

Biomedicines 2025, 13(9), 2252; https://doi.org/10.3390/biomedicines13092252 (registering DOI) - 12 Sep 2025

Abstract

Lichen sclerosus (LS) is a chronic, relapsing skin disease that predominantly affects the perineal and genital regions, although extragenital manifestations can occur. Despite its significant impact on patients’ quality of life, particularly affecting sexual and urinary function, LS remains underdiagnosed. Multiple factors, including [...] Read more.

Lichen sclerosus (LS) is a chronic, relapsing skin disease that predominantly affects the perineal and genital regions, although extragenital manifestations can occur. Despite its significant impact on patients’ quality of life, particularly affecting sexual and urinary function, LS remains underdiagnosed. Multiple factors, including genetic predisposition, hormonal changes, immunological abnormalities, trauma, and urine irritation, contribute to its development and persistence. This review aims to clarify the complex pathophysiology of LS by exploring three main mechanisms: autoimmune dysregulation, sclerotic tissue formation, and oxidative stress. Autoimmune dysregulation involves T-cell infiltration and the roles of miR-155 and extracellular matrix protein 1 dysfunction, leading to chronic inflammation. miR-155 contributes to sclerotic tissue formation alongside galectin-7, promoting fibroblast proliferation and collagen synthesis. Oxidative stress results in tissue damage, autoimmunity, chronic inflammation, and an increased risk of carcinogenesis. Understanding these mechanisms is crucial for developing targeted therapies and improving LS management. Further research is needed to unravel the genetic basis, immune responses, and interactions between key mediators, ultimately advancing innovative therapeutic strategies and precision medicine in LS. Full article

(This article belongs to the Special Issue Pathogenesis and Targeted Therapy of Autoimmune Diseases)

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12 pages, 503 KB

Open AccessArticle

Interferon Regulator Factor 5: A Novel Inflammatory Marker and Promising Therapeutic Target in Ulcerative Colitis

by Karima Farrag, Aysegül Aksan, Marina Korotkova, Helena Idborg, Per-Johan Jakobsson, Andreas Weigert, Michael Vieth, Stefan Zeuzem, Irina Blumenstein and Jürgen Stein

Biomedicines 2025, 13(9), 2251; https://doi.org/10.3390/biomedicines13092251 (registering DOI) - 12 Sep 2025

Abstract

Background: Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation affecting the gastrointestinal tract and extraintestinal organs. The etiology of IBD is multifactorial, involving genetic, immunological, and environmental factors. Over 200 genetic loci have been [...] Read more.

Background: Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation affecting the gastrointestinal tract and extraintestinal organs. The etiology of IBD is multifactorial, involving genetic, immunological, and environmental factors. Over 200 genetic loci have been associated with the disease, indicating a significant genetic predisposition. Despite advances in understanding its genetic basis, clinical management remains challenging due to heterogeneity in disease presentation and variable treatment responses. Current therapies, such as 5-aminosalicylates and biologics, are not universally effective, underscoring the need for reliable biomarkers to predict therapeutic responses. Objective: This study investigates the potential role of interferon regulatory factor 5 (IRF5) in the pathogenesis of IBD, with a particular focus on UC. Methods: We conducted a systematic analysis of colon biopsies from 30 adult patients diagnosed with UC and from 8 non-IBD controls. Immunostaining was performed to assess IRF5 expression in colonic tissues using the primary IRF5 antibody (1:300, Abcam, ab181553). Statistical analyses evaluated the correlation between IRF5-positive cell counts, disease activity, and inflammatory markers such as calprotectin. Results: Our analysis revealed a significant increase in IRF5-positive macrophage-like cells in the inflamed mucosa of IBD patients compared to healthy controls. The number of IRF5-positive cells showed a positive correlation with disease activity and calprotectin levels, indicating that higher IRF5 expression is associated with increased inflammation. Conclusion: This study demonstrates a significant correlation between IRF5 expression and disease activity in UC, suggesting that IRF5 may play a crucial role in the inflammatory processes of the disease. The findings propose IRF5 as a novel biomarker for therapeutic intervention in IBD. Further research is needed to clarify the mechanisms by which IRF5 contributes to IBD pathogenesis and to explore the therapeutic potential of targeting this pathway in clinical settings Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)

13 pages, 1629 KB

Open AccessArticle

Sex-Stratified Prediction Models for 5-Year Nonalcoholic Fatty Liver Disease Risk in Thyroid Cancer Patients: A Nationwide Cohort Study

by Young Bin Cho and Kyoung Sik Park

Biomedicines 2025, 13(9), 2250; https://doi.org/10.3390/biomedicines13092250 - 12 Sep 2025

Abstract

Background/Objectives: Nonalcoholic fatty liver disease (NAFLD) is a significant complication among survivors of thyroid cancer; however, existing prediction models for NAFLD remain inadequate. Our objective was to develop survival prediction models for 5-year risk of NAFLD in patients diagnosed with thyroid cancer. [...] Read more.

Background/Objectives: Nonalcoholic fatty liver disease (NAFLD) is a significant complication among survivors of thyroid cancer; however, existing prediction models for NAFLD remain inadequate. Our objective was to develop survival prediction models for 5-year risk of NAFLD in patients diagnosed with thyroid cancer. Methods: Utilizing the Korean National Health Insurance Service claims database, we selected 3644 post-thyroidectomy patients with thyroid cancer between 2004 and 2014. Following a 7:3 stratified division into training and test datasets, we developed sex-stratified survival models using random survival forest (RSF) and Cox proportional hazards regression (Cox). The evaluation of prediction models was performed using Harrell’s concordance index (C-index), time-dependent area under the curve (AUC), and risk stratification analysis. Results: In the female cohort, the Cox model exhibited a superior C-index of 0.67 (95% CI 0.61–0.72), surpassing the RSF model, which had a C-index of 0.62 (95% CI 0.57–0.68). Notably, age-stratified Cox models for females demonstrated enhanced performance compared to the unstratified female Cox model. Conversely, male-specific models did not show significant performance in NAFLD. Risk stratification analysis revealed that the female-specific models effectively categorized patients into low- and high-risk groups, with statistical significance (p < 0.001). Conclusions: This study constructed well-performing time-to-event prediction models for NAFLD of female patients with thyroid cancer, which is significant in risk stratification. Full article

(This article belongs to the Special Issue Advances in Precision Oncology for Thyroid Carcinoma: Integrating Artificial Intelligence, Genomics and Molecular Diagnostics)

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27 pages, 432 KB

Open AccessReview

Magnesium and Zinc in Schizophrenia

by Mihai Nechifor

Biomedicines 2025, 13(9), 2249; https://doi.org/10.3390/biomedicines13092249 - 12 Sep 2025

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Abstract

Schizophrenia is a severe recurrent chronic disease that affects a large number of patients. Numerous genetic and epigenetic factors are involved in the pathogenesis of this disease. The involvement of magnesium and zinc has been relatively little studied and often underestimated. The main [...] Read more.

Schizophrenia is a severe recurrent chronic disease that affects a large number of patients. Numerous genetic and epigenetic factors are involved in the pathogenesis of this disease. The involvement of magnesium and zinc has been relatively little studied and often underestimated. The main mechanisms by which zinc and magnesium are involved in the pathogenesis of these diseases is their influence on the neurotransmitter systems at the cerebral level (dopaminergic, glutamatergic, serotoninergic, GABAergic, catecholaminergic and cannabinoid systems). The action of many other factors involved in one form or another in the pathogenesis of schizophrenia is influenced by magnesium and zinc. Among these factors, we mention neuroinflammation, oxidative stress, nuclear factor kB (NF-kappaB), galanin, brain-derived neurotrophic factor (BDNF), substance P(SP), oxytocin, ACTH, prolactin and others. There are also data related to some interactions between antipsychotic medication and the two cations, as well as to disturbed physiological processes (sleep, appetite) in patients with schizophrenia. The existing data show that the concentrations of the two cations must always be determined and the deficits immediately corrected. Full article

(This article belongs to the Section Molecular and Translational Medicine)

16 pages, 1552 KB

Open AccessReview

Role of CD138⁺ Plasma Cells and Natural Killer Cells in Couple Infertility: A Review

by Alessandro Messina, Alessandro Libretti, Ilaria Giovannini, Livio Leo, Valentino Remorgida, Bianca Masturzo and Raffaele Tinelli

Biomedicines 2025, 13(9), 2248; https://doi.org/10.3390/biomedicines13092248 - 12 Sep 2025

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Abstract

Couple infertility is a multifactorial condition that involves, among other factors, immunological alterations of the endometrium. CD138⁺ plasma cells and uterine Natural Killer (NK) cells have been associated with implantation failures and recurrent pregnancy loss, although the literature presents considerable heterogeneity in [...] Read more.

Couple infertility is a multifactorial condition that involves, among other factors, immunological alterations of the endometrium. CD138⁺ plasma cells and uterine Natural Killer (NK) cells have been associated with implantation failures and recurrent pregnancy loss, although the literature presents considerable heterogeneity in findings. This narrative review aims to synthesize current evidence on the role of these two immunological biomarkers in the pathophysiology of infertility. According to the current literature, the presence of CD138⁺ plasma cells was strongly associated with chronic endometritis and adverse reproductive outcomes, with improvement following targeted antibiotic therapy. NK cells, particularly in their hyperactive peripheral form, were elevated in infertile women, although data on uterine NK cells remain controversial. Recent studies suggest a possible interaction between chronic inflammation and NK dysfunction. A combined evaluation of CD138⁺ and NK cells may represent an integrated diagnostic approach in idiopathic infertility. Prospective studies are needed to standardize cut-off values and validate these markers in clinical practice. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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31 pages, 412 KB

Open AccessReview

Non-Pharmacological Treatment Methods of Lennox–Gastaut Syndrome—Review of the Literature

by Piotr Duda, Michał Granat, Stanisław J. Czuczwar and Barbara Miziak

Biomedicines 2025, 13(9), 2247; https://doi.org/10.3390/biomedicines13092247 - 12 Sep 2025

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Abstract

Lennox–Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy, often associated with pharmacoresistance. As complete seizure control is usually not achievable with the use of drug therapy, non-pharmacological treatment may be offered to intractable patients. In this review, we are going to [...] Read more.

Lennox–Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy, often associated with pharmacoresistance. As complete seizure control is usually not achievable with the use of drug therapy, non-pharmacological treatment may be offered to intractable patients. In this review, we are going to present literature reports on various non-pharmacological treatments, including surgical and dietary methods. Surgical interventions, such as resective surgery, corpus callosotomy (CC), or neuromodulation therapies such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), can be offered to pharmacoresistant patients. If the epileptogenic area can be detected, resective surgery is a treatment of choice. On the contrary, if non-invasive and invasive diagnostic methods fail to detect epileptogenic lesions, CC and VNS are considered palliative surgical methods. While both CC and VNS are considered effective in seizure reduction, CC is still more popular than VNS, although VNS seems to be related to better tolerability. Although all neuromodulation therapies require multidirectional optimization, DBS appears to be particularly promising for LGS. The classic ketogenic diet (cKD) is considered an effective and well-tolerated method in LGS treatment. The modified Atkins diet (MAD) and the low glycemic index treatment (LGIT) could be used as valuable alternatives due to their lower restrictiveness and better tolerability. Moreover, combinations of several treatment methods could significantly improve LGS patients’ seizure outcomes. Full article

(This article belongs to the Special Issue Epilepsy: Pathomechanism, Diagnostics, and Novel Treatment Options)

19 pages, 4559 KB

Open AccessArticle

Genetic Variants and Soluble Isoforms of PD-1/PD-L1 as Novel Biomarkers for Pancreatic Ductal Adenocarcinoma (PDAC) Susceptibility and Prognosis

by Marwa Hassan, Walaa H. El-Maadawy, Yasmine Elhusseny, Fatma Elbatol Agamy, Sally A. Fahim and Mahmoud Balata

Biomedicines 2025, 13(9), 2246; https://doi.org/10.3390/biomedicines13092246 - 12 Sep 2025

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm often diagnosed at advanced stages. Immune checkpoint molecules, particularly programmed cell death protein-1 (PD-1) and its ligand PD-L1, are pivotal in tumor immune evasion. Genetic polymorphisms in PD-1/PD-L1 and their soluble isoforms (sPD-1/sPD-L1) [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm often diagnosed at advanced stages. Immune checkpoint molecules, particularly programmed cell death protein-1 (PD-1) and its ligand PD-L1, are pivotal in tumor immune evasion. Genetic polymorphisms in PD-1/PD-L1 and their soluble isoforms (sPD-1/sPD-L1) may influence individual susceptibility to cancer and disease progression. Therefore, this study was conducted to examine the correlation between PD-1/PD-L1 gene polymorphisms, serum levels of sPD-1/sPD-L1, and their association with PDAC susceptibility, severity, and prognostication. Methods: This case–control study was performed with 150 PDAC patients and 150 controls. Clinical and laboratory data, including tumor markers (CA19-9 and CEA), were recorded. Allele-specific PCR was utilized to genotype PD-1 (rs6749527 and rs7421861) and PD-L1 (rs2297136, and rs4143815). sPD-1/sPD-L1 were quantified with ELISA. Mapping of the Kaplan–Meier survival curve of mutant genes was performed. Results: The rs7421861 AG and GG and rs4143815 GG genotypes, together with their G-alleles, were linked to increased PDAC risk and greater tumor burden. In contrast, the rs2297136 GG genotype and G-allele conferred protection against PDAC development. Serum sPD-L1 levels, rather than sPD-1, were markedly elevated in PDAC patients, progressively increased with tumor grade, and correlated with tumor markers. Also, higher PD-L1 gene expression was associated with lower overall survival. Conclusions: PD-1/PD-L1 genetic variants, particularly rs7421861 and rs4143815, along with sPD-L1 levels, correlate with PDAC susceptibility and disease severity. These findings endorse the prospects of integrating immune checkpoint genetic variants and soluble biomarkers for early identification, risk stratification, prognostication, and personalized therapeutic strategies in PDAC management. Full article

(This article belongs to the Special Issue Advances in Liquid Biopsy from Technological Innovation to Therapeutic Intervention)

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19 pages, 4733 KB

Open AccessArticle

Unraveling the Functional Impact of Splicing Variants in Inherited Hearing Disorders Through Minigene Splicing Assays

by Lara Emily Rosso, Giulia Pianigiani, Anna Morgan, Elisa Rubinato, Elisa Paccagnella, Stefania Lenarduzzi, Anita Wischmeijer, Beatrice Spedicati and Giorgia Girotto

Biomedicines 2025, 13(9), 2245; https://doi.org/10.3390/biomedicines13092245 - 11 Sep 2025

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Abstract

Background/Objectives: Hereditary hearing loss (HHL) is a genetically heterogeneous condition, involving more than 150 genes in non-syndromic cases and associated with over 400 distinct disorders in syndromic forms. Although whole-exome sequencing (WES) has markedly increased diagnostic yield, a substantial number of cases [...] Read more.

Background/Objectives: Hereditary hearing loss (HHL) is a genetically heterogeneous condition, involving more than 150 genes in non-syndromic cases and associated with over 400 distinct disorders in syndromic forms. Although whole-exome sequencing (WES) has markedly increased diagnostic yield, a substantial number of cases remain unsolved, often due to intronic variants that affect splicing and are difficult to interpret. This study aimed to characterize the potential impact of intronic variants predicted to alter splicing in families affected by HHL. Methods: The effect of seven intronic variants, previously identified in a diagnostic setting by WES within ADGRV1, ATP11A, GSDME, OTOF, OTOGL, and USH2A genes, was evaluated. To functionally validate these predictions, in vitro minigene splicing assays were subsequently performed. Results: All the identified variants were predicted to disrupt normal RNA splicing. The functional studies with minigene assays confirmed this observation and showed that the tested variants induced both exon skipping and activation of cryptic splice sites. In five out of seven cases, these splicing alterations caused a frameshift and introduced a premature termination codon, ultimately resulting in nonsense-mediated mRNA decay and protein degradation. Conclusions: This study expands the mutational spectrum of HL-related genes and highlights the importance of integrating in silico predictions with minigene assays. Such a combined approach is crucial for accurate interpretation of splicing variants, particularly when patient-derived RNA samples are unavailable. Full article

(This article belongs to the Special Issue The Molecular Mechanisms of Hearing, Balance and Deafness)

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19 pages, 4406 KB

Open AccessArticle

L-Citrulline Improves Recovery of Enterocytes While Not Affecting Gut Microbiota in an In Vitro Model of Chemotherapy-Induced Gastrointestinal Mucositis

by Wally van der Laan, Pablo A. Gallardo Molina, Debby P. Y. Koonen, Hermie J. M. Harmsen and Wim J. E. Tissing

Biomedicines 2025, 13(9), 2244; https://doi.org/10.3390/biomedicines13092244 - 11 Sep 2025

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Abstract

Background/Objectives: Despite significant advancements in cancer treatment outcomes, side effects, such as gastrointestinal mucositis (GIM), continue to impair patients’ quality of life. The recent literature suggests L-citrulline as a novel treatment for GIM. However, no in vitro model to study the potential for [...] Read more.

Background/Objectives: Despite significant advancements in cancer treatment outcomes, side effects, such as gastrointestinal mucositis (GIM), continue to impair patients’ quality of life. The recent literature suggests L-citrulline as a novel treatment for GIM. However, no in vitro model to study the potential for L-citrulline as a treatment for GIM is currently available, and the effect of L-citrulline on the gut microbiota remains unclear. This study aims to propose a suitable in vitro model to study the effect of L-citrulline on the gut microbiota and to determine whether it can mitigate GIM. Methods: The CaCo-2 and T84 cell lines were cultured using cell impedance assays and treated with different doses of methotrexate and melphalan to select an appropriate model for L-citrulline research. The selected model was further used to investigate the impact of L-citrulline on gut microbiota cultured using microbial culture assays containing YCFAG. Results: Neither CaCo-2 nor T84 cells treated with methotrexate were suitable models for our study due to varying responses to treatment. T84 cells treated with 100 μg/mL melphalan demonstrated a consistent response, making them a suitable model for in vitro research on treatments for GIM. The use of L-citrulline demonstrated potential protective effects, as melphalan-treated enterocytes showed less cellular damage in its presence and slightly reduced enteroaggregative E. coli growth. Conclusions: L-Citrulline supplementation reduced epithelial cell injury due to melphalan, suggesting therapeutic potential. Further testing is required to determine its efficacy in vivo and clarify the mechanisms underlying this potential benefit. Full article

(This article belongs to the Special Issue Pediatric Tumors: Diagnosis, Pathogenesis, Treatment, and Outcome)

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30 pages, 875 KB

Open AccessReview

MicroRNA Landscape in Hepatocellular Carcinoma: Metabolic Re-Wiring, Predictive and Diagnostic Biomarkers, and Emerging Therapeutic Targets

by Dimitris Liapopoulos, Panagiotis Sarantis, Theodora Biniari, Thaleia-Eleftheria Bousou, Eleni-Myrto Trifylli, Ioanna A. Anastasiou, Stefania Kokkali, Dimitra Korakaki, Spyridon Pantzios, Evangelos Koustas, Ioannis Elefsiniotis and Michalis V. Karamouzis

Biomedicines 2025, 13(9), 2243; https://doi.org/10.3390/biomedicines13092243 - 11 Sep 2025

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Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response [...] Read more.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC. Full article

(This article belongs to the Special Issue New Insights into the Diagnosis and Treatment of Hepatocellular Carcinoma—2nd Edition)

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43 pages, 2573 KB

Open AccessReview

Polymorphisms in VEGF Signaling Pathway Genes and Their Potential Impact on Type 2 Diabetes Mellitus and Associated Complications: A Scoping Review

by Christiane Mayrhofer Grocoske de Lima, Rafaela Cirillo de Melo, Nathalia Marçallo Peixoto Souza, Paula Rothbarth Silva, Dayane Ferreira Aguiar, Luana Mota Ferreira, Waldemar Volanski, Geraldo Picheth, Fabiane Gomes de Moraes Rego and Marcel Henrique Marcondes Sari

Biomedicines 2025, 13(9), 2242; https://doi.org/10.3390/biomedicines13092242 - 11 Sep 2025

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Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic and multifactorial metabolic disorder associated with genetic and environmental factors. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and vascular homeostasis, and genetic polymorphisms in the VEGF signaling pathway have [...] Read more.

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a chronic and multifactorial metabolic disorder associated with genetic and environmental factors. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and vascular homeostasis, and genetic polymorphisms in the VEGF signaling pathway have been linked to the T2DM development, progression, and complications. This scoping review investigated the association between VEGF gene and VEGF receptors single-nucleotide polymorphisms (SNPs) and susceptibility to T2DM and vascular complications. Methods: A thorough systematic review was performed utilizing scientific databases (PubMed, Web of Science, and Scopus) in March 2025. From an initial pool of 796 records, 59 relevant articles were selected for inclusion in the analysis. Results: The most frequently studied SNPs were rs2010963 (31/59), rs699947 (16/59), rs3025039 (15/59), rs833061 (11/59), rs1570360 (7/59) in the VEGFA gene and rs2071559(6/59) in VEGFR2. The studies include a diverse range of ethnic groups, including Asian, European and Middle Eastern populations. The main complications associated with these SNPs were microvascular conditions such as diabetic retinopathy (DR) (49/59), diabetic neuropathy (DPN) (6/59), diabetic nephropathy (DNP) (2/59), and as well as macrovascular complications including diabetic foot ulcers (DFU) (10/59). The results revealed that these polymorphisms, particularly rs3025039 and rs2010963, were more consistently associated with microvascular complications such as DR rather than with T2DM itself. The C allele of rs2010963 was associated with increased risk of DR in Indian populations, while no such association was observed in European. Similarly, the T allele of rs3025039 conferred protection against DPN in a Chinese population but was associated with higher DR risk in an Indian study, suggesting that the same allele may play distinct roles depending on ethnic background and clinical phenotype. Conclusions: VEGF signaling pathway genetic polymorphisms demonstrate potential as biomarkers for diabetic complications, especially microvascular outcomes. The findings suggest a genetic basis for differences in complications of T2DM. Future studies should investigate relevant SNPs across diverse ethnic groups to better understand genetic risks associated with the disease and its vascular complications. Full article

(This article belongs to the Special Issue Biomarkers in Metabolic Disorders, Obesity and Type 2 Diabetes Mellitus—2nd Edition)

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13 pages, 1067 KB

Open AccessArticle

Modalities Differentiation of Pain Perception Following Ischemic Stroke: Decreased Pressure Pain Perception

by Yongkang Zhi, Chen Zhao, Yu Zhang, Jianzhang Ni, Ming Zhang, Dongsheng Fan and Yazhuo Kong

Biomedicines 2025, 13(9), 2241; https://doi.org/10.3390/biomedicines13092241 - 11 Sep 2025

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Abstract

Background/Objectives: Ischemic stroke frequently leads to somatosensory impairments and abnormal pain perception. Meanwhile, pain perception can be evoked through multiple somatosensory modalities, each mediated by distinct neural pathways. Despite this understanding, current research investigating stroke-induced alterations in pain perception across different modalities [...] Read more.

Background/Objectives: Ischemic stroke frequently leads to somatosensory impairments and abnormal pain perception. Meanwhile, pain perception can be evoked through multiple somatosensory modalities, each mediated by distinct neural pathways. Despite this understanding, current research investigating stroke-induced alterations in pain perception across different modalities of noxious stimulation remains insufficient, particularly concerning responses to varying stimulus intensities (including both sub-threshold and supra-threshold levels). Methods: In this study (March 2023 to July 2024), we enrolled 30 ischemic stroke patients and 35 matched controls and employed two modalities of noxious stimuli (e.g., heat stimuli were delivered using the Medoc CHEPS and pressure stimuli were administered via an MRI-Compatible Foot-Sole Stimulator) to systematically evaluate post-stroke changes in pain perception through two experiments. We compared self-reported pain sensitivity, somatosensory thresholds (i.e., warmth and pressure), and pain thresholds (i.e., heat and pressure pain) between ischemic stroke patients and healthy controls in Experiment 1. We focused on pain perception when participants simultaneously experienced heat and pressure in Experiment 2. Results: Experiment 1 showed an absence of a significant correlation between heat and pressure pain thresholds in stroke patients, but this correlation could be observed in healthy controls. Notably, stroke patients had an impairment in pain perception of pressure stimulation at supra-threshold intensities. Experiment 2 observed a similar facilitative pain integration in patients as healthy controls when they perceived heat and pressure stimuli jointly and simultaneously. Conclusions: These findings provide valuable insights into pain perception following a stroke, highlighting the need for tailored evaluation strategies considering the differences in somatosensory modality damage. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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17 pages, 1495 KB

Open AccessReview

Risk for COVID-19 Vulnerability in Patients with Inflammatory Bowel Disease: Assessing Alterations in ACE2 and TMPRSS2

by Jorge Sáez-Leyva, Matthew P. Lennol, Carlos Avilés-Granados, María-Salud García-Ayllón and Javier Sáez-Valero

Biomedicines 2025, 13(9), 2240; https://doi.org/10.3390/biomedicines13092240 - 11 Sep 2025

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Abstract

Chronic inflammatory conditions often involve the dysregulation of key enzymes, including serine proteases such as transmembrane serine protease 2 (TMPRSS2) and the angiotensin converting enzyme 2 (ACE2), which are key proteins implicated in the cellular entry mechanism of SARS-CoV-2. It remains uncertain whether [...] Read more.

Chronic inflammatory conditions often involve the dysregulation of key enzymes, including serine proteases such as transmembrane serine protease 2 (TMPRSS2) and the angiotensin converting enzyme 2 (ACE2), which are key proteins implicated in the cellular entry mechanism of SARS-CoV-2. It remains uncertain whether the gastrointestinal symptoms observed in COVID-19 patients result from direct viral infection of the gastrointestinal tract, a process that may be exacerbated by altered expression of ACE2 or TMPRSS2. In this review, we explore the interplay among ACE2 and TMPRSS2 in the context of inflammatory bowel disease (IBD), including their roles in disease pathology and response to therapy. We also examine methodological approaches for assessing whether protease alterations contribute to increased susceptibility to infection, considering that TMPRSS2 exists in inactive (zymogen) and active forms. Furthermore, while membrane-bound ACE2 facilitates viral entry, soluble ACE2 fragments may act as decoys, preventing virus–receptor interaction. Therefore, the interpretation of changes in full-length versus cleaved forms of ACE2 and related enzymes is critical for understanding vulnerability to SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Crohn’s Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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12 pages, 558 KB

Open AccessSystematic Review

Arthrospira platensis and Its Potential for Skin Regeneration in Animal Models as Support for Initiating Clinical Trials in Humans: A Systematic Review

by Sara Isabel Fernández, María Estefanía Hernández and Lina Andrea Gómez

Biomedicines 2025, 13(9), 2239; https://doi.org/10.3390/biomedicines13092239 - 11 Sep 2025

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Abstract

Background/Objectives: The search for natural alternatives to enhance wound healing has driven the investigation of bioactive compounds, such as Spirulina. This microalga, rich in antioxidant, anti-inflammatory, and antimicrobial properties, contains compounds like phycocyanin (C-PC), which promote cell repair, reduce inflammatory markers, and [...] Read more.

Background/Objectives: The search for natural alternatives to enhance wound healing has driven the investigation of bioactive compounds, such as Spirulina. This microalga, rich in antioxidant, anti-inflammatory, and antimicrobial properties, contains compounds like phycocyanin (C-PC), which promote cell repair, reduce inflammatory markers, and combat bacteria. Although its effects are promising, its efficacy still requires validation through human clinical trials. This article aims to review scientific publications on the use of Spirulina in skin regeneration using animal wound models. Methods: A database search was conducted for studies published between 2017 and 2024 on the effects of Spirulina on tissue regeneration in rats, chosen for their genetic similarity to humans. In vitro studies, those using other animal models, or studies published in languages other than Spanish or English were excluded. The review followed the PRISMA 2020 guidelines. Results: Four studies were analyzed, all of which demonstrated promising results in wound healing in rats. Spirulina was administered through oral supplements, hydrogels, and nanophytosomal formulations. These treatments accelerated wound closure and improved granulation tissue formation, vascularization, and epithelialization. Additionally, they exhibited antihyperglycemic effects in diabetic rats. Conclusions: The reviewed studies highlight the potential of Spirulina platensis to enhance wound healing, particularly in cases of diabetes and burns. Its antioxidant and anti-inflammatory properties play a crucial role in accelerating cellular regeneration and reducing inflammation, contributing to faster and more effective recovery. However, further research in humans is necessary to confirm its safety and clinical efficacy. Full article

(This article belongs to the Special Issue Wound Healing: From Basic to Clinical Research)

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19 pages, 7292 KB

Open AccessArticle

Association of HTR1F with Prognosis, Tumor Immune Microenvironment, and Drug Sensitivity in Cancer: A Multi-Omics Perspective

by Yanjun Gao, Ziyue Zhang, Dafu Ye, Qingqing Li, Yingmei Wen, Shaowen Ma, Bo Zheng, Lei Chen and Yi Yao

Biomedicines 2025, 13(9), 2238; https://doi.org/10.3390/biomedicines13092238 - 11 Sep 2025

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Abstract

Background: HTR1F (5-Hydroxytryptamine Receptor 1F) encodes a G protein-coupled receptor involved in serotonin signaling. Although dysregulated HTR1F expression has been implicated in certain malignancies, its biological functions and clinical significance across cancer types remain largely unexplored. Methods: We performed an integrative pan-cancer [...] Read more.

Background: HTR1F (5-Hydroxytryptamine Receptor 1F) encodes a G protein-coupled receptor involved in serotonin signaling. Although dysregulated HTR1F expression has been implicated in certain malignancies, its biological functions and clinical significance across cancer types remain largely unexplored. Methods: We performed an integrative pan-cancer analysis of transcriptomic and pharmacogenomic datasets covering 34 cancer types (PAN-CAN cohort, N = 19,131; normal tissues, G = 60,499). Drug sensitivity and molecular docking analyses were conducted using the GSCALite database. The protein–protein interaction (PPI) network of HTR1F was constructed via the STRING database. Additionally, we evaluated the effects of HTR1F overexpression on proliferation and invasion in human lung squamous cell carcinoma (LUSC) cell lines NCI-H520 and NCI-H226. Results: HTR1F expression was significantly upregulated in 17 cancer types and was associated with poor prognosis, with LUSC showing an AUC of 0.912 for 1-year survival prediction. In LUSC, 695 genes were upregulated and 67 downregulated in response to HTR1F overexpression. HTR1F expression correlated with immune-related genes, immune checkpoints, tumor-infiltrating immune cells, tumor mutation burden (TMB), microsatellite instability (MSI), and drug responses. Genomic alterations, including amplification and deletion, were positively associated with HTR1F expression. Drug sensitivity analysis identified compounds such as sotrastaurin (−10.2 kcal/mol), austocystin D (−9.7 kcal/mol), and tivozanib (−9.3 kcal/mol) as potentially effective inhibitors based on predicted binding affinity. Functional enrichment analyses (GO, KEGG) and GSEA revealed that HTR1F is primarily involved in cell cycle regulation, DNA replication, cellular senescence, and immune-related pathways. Functional validation showed that HTR1F overexpression promotes proliferation of LUSC cells via the MAPK signaling pathway. Conclusions: Our integrative analysis highlights HTR1F as a potential biomarker associated with prognosis, immune modulation, and drug sensitivity across multiple cancer types. These findings provide a foundation for future experimental and clinical studies to explore HTR1F-targeted therapies. Full article

(This article belongs to the Special Issue Advanced Research in Anticancer Inhibitors and Targeted Therapy)

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19 pages, 2154 KB

Open AccessArticle

Association of LPCAT1*rs9728 Variant with Reduced Susceptibility to Neonatal Respiratory Distress Syndrome

by Shimaa Dorgham, Sohier Yahia, Doaa Shahin, Ahmad M. Eita, Eman A. Toraih and Rami M. Elshazli

Biomedicines 2025, 13(9), 2237; https://doi.org/10.3390/biomedicines13092237 - 11 Sep 2025

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Abstract

Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling [...] Read more.

Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the LPCAT1*rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. Methods: The LPCAT1 (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the LPCAT1 gene was elucidated using bioinformatic approaches. Results: The LPCAT1*rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, p = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, p = 0.416). Apgar score and Silverman–Andersen respiratory severity score (RSS) were statistically significant with prematurity classes (p < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. Conclusions: This research exhibited a significant difference between the LPCAT1 (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates. Full article

(This article belongs to the Special Issue New Insights in Respiratory Diseases)

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13 pages, 449 KB

Open AccessArticle

TCF Plus Radiochemotherapy Versus Neoadjuvant Radiochemotherapy Versus Flot Perioperative Chemotherapy in Esophageal Adenocarcinoma: The Results of a Three-Cohort, Multi-Centric Comparison: The A4 Study

by Marco Lorenzo Bonù, Giulia Volpi, Gloria Zanni, Jacopo Balduzzi, Fabrizia Terraneo, Giusto Pignata, Giuseppina Arcangeli, Francesco Frassine, Paola Vitali, Eliana La Rocca, Simone Giacopuzzi, Jacopo Weindelmayer, Carlo Alberto De Pasqual, Martina Milazzo, Michele Pavarana, Valentina Zen, Stefano De Pascale, Uberto Fumagalli Romario, Michela Buglione and Giovanni De Manzoni

Biomedicines 2025, 13(9), 2236; https://doi.org/10.3390/biomedicines13092236 - 11 Sep 2025

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Introduction: Recent randomized evidence suggests that stage II–IV non metastatic esophageal adenocarcinoma is best managed with perioperative chemotherapy (CHT) and surgery. Intensification of neoadjuvant chemotherapy and radiochemotherapy are proposed before surgery in high-volume centers with the aim of increasing both systemic and locoregional [...] Read more.

Introduction: Recent randomized evidence suggests that stage II–IV non metastatic esophageal adenocarcinoma is best managed with perioperative chemotherapy (CHT) and surgery. Intensification of neoadjuvant chemotherapy and radiochemotherapy are proposed before surgery in high-volume centers with the aim of increasing both systemic and locoregional control. However, few data comparing intensified RTCHT, CHT plus RTCHT and perioperative CHT with FLOT in real-life scenarios are available. Methods: This is a multicenter, retrospective series, including three cohorts of patients treated for esophageal adenocarcinoma: Cohort A: nRTCHT; Cohort B: TCF plus RTCHT, defined as triplet chemotherapy followed by dose-reduced triplet therapy + RT; Cohort C: perioperative chemotherapy with FLOT regimen. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were pathologic complete response (pCR), pathologic lymph-node complete response (ypN0), overall survival (OS), and perioperative acute toxicity. Results: From January 2013 to December 2023, 142 patients were identified. All patients received multimodal therapy with radical esophagectomy. A total of 95% of patients were male; the majority of patients presented with stage cT3cN1. A total of 63 patients were treated in Cohort A (31 cases with doublet 5FU-CDDP concurrent to 50.4 Gy and 32 cases with CROSS regimen), 36 in Cohort B, and 43 in Cohort C. After a median FU of 36 months, the 3-year DFS resulted 58.6%. pCR occurred in 26 cases (18.6%). Three-year OS had a value of 72%. At univariate analysis, ypN0 was related to better DFS; cN+ disease was related with worse OS. The treatment cohort did not impact survival outcomes; however, an effect on CR was shown, with pCR in 15% (A), 36.3% (B), 11% (C) of cases, respectively (χ: 0.008). A total of 67% of patients in Cohort B experienced a ypN0. Two treatment-related deaths occurred (one in Cohort A and one in C) with a slight increase in G3 toxicity in cohort C. Conclusions: In this real-life multicenter series, oncological results were adequate for all three neoadjuvant strategies. TCF plus RTCHT guaranteed a higher pCR and ypN0 rate without increasing toxicity. An intensified neoadjuvant schedule, such as TCF plus RTCHT, may be useful in cases where higher tumor and nodal responses are needed. Taken together, our data highlight that further investigation is warranted before abandoning radiotherapy-based neoadjuvant approaches in esophageal and GEJ adenocarcinoma. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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12 pages, 3375 KB

Open AccessArticle

Optical and Scanning Electron Microscopy Thrombus Findings in Patients with STEMI Undergoing Primary Versus Rescue PCI

by Stella Marinelli Pedrini, Thiago P. A. Aloia, André H. Aguillera, Paula M. P. S. Gomes, Jamil R. Cade, Francisco Sandro Menezes-Rodrigues, Bárbara P. Freitas, Marco T. Souza, Francisco A. H. Fonseca, Marcos Danillo Oliveira, Breno O. Almeida, Andrey J. Serra, Renato D. Lopes, Rita Sinigaglia-Coimbra and Adriano Caixeta

Biomedicines 2025, 13(9), 2235; https://doi.org/10.3390/biomedicines13092235 - 11 Sep 2025

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Abstract

Background: The mechanisms underlying fibrinolysis failure in patients with STEMI who are undergoing a pharmacoinvasive strategy appear to be multifactorial and may be associated with the thrombus’s architecture and composition. Objective: We aimed to compare the thrombus composition in patients with [...] Read more.

Background: The mechanisms underlying fibrinolysis failure in patients with STEMI who are undergoing a pharmacoinvasive strategy appear to be multifactorial and may be associated with the thrombus’s architecture and composition. Objective: We aimed to compare the thrombus composition in patients with STEMI who were undergoing rescue percutaneous coronary intervention (rPCI) versus primary PCI (pPCI) using optical microscopy (OM) and scanning electron microscopy (SEM). Methods: Fifty-three patients were prospectively enrolled, with twenty-five undergoing rPCI and twenty-eight undergoing pPCI. After thrombus aspiration, each harvested fragment was divided into two pieces: one was analyzed using OM with a 60× magnifying lens on hematoxylin–eosin-stained samples, and the other with SEM at 5000× magnification. Results: Patients who underwent rPCI had significantly higher C-reactive protein levels and a longer ischemic interval at admission compared to those treated with pPCI (9.92 h [range: 1.58–106.17] vs. 2.14 h [range: 0–48]; p < 0.001). Optical microscopy analysis revealed that thrombi from rPCI patients exhibited a significantly higher erythrocyte area percentage (18.36% [range: 0.3–50.08] vs. 0.91% [range: 0–70.1]; p = 0.001), a lower fibrin content as assessed by optical microscopy (79.49% [range: 49.2–98.25] vs. 94.43% [range: 29.19–99.92]; p = 0.006), and a greater amount of cholesterol crystals as measured by SEM (1.73 μm² [range: 0–18.51] vs. 0.08 μm² [range: 0–0.71]; p < 0.001). Conclusions: The thrombus composition of patients with STEMI who are undergoing rPCI had higher amounts of erythrocytes and cholesterol crystals and a lesser area occupied by fibrin compared to those undergoing pPCI. The composition of thrombi in rPCI could potentially contribute to the failure of fibrinolytic therapy within a pharmacoinvasive strategy. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Heart Failure and Cardiomyopathy)

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Biomedicines, Volume 13, Issue 9 (September 2025) – 221 articles

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